GENITALIA OUTGROWTH AND HYPOSPADIAS

生殖器生长和尿道下裂

基本信息

批准号：
9317645
负责人：
Liang Ma
金额：
$ 34.31万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9317645
关键词：
Alleles Androgen Receptor Androgens Awareness Congenital Abnormality Development Embryonic Development Endocrine Disruptors Environmental Risk Factor Etiology Event Exposure to Fibroblast Growth Factor Receptors Foundations Frequencies Future Genes Genetic Genetic Transcription Genital system Genitalia Goals Hand Heart Abnormalities Human Hypospadias Incidence Knockout Mice Knowledge Lead Limb structure Mammals Masculine Mesenchyme Methods Molecular Genetics Molecular Profiling Morphogenesis Mus Mutant Strains Mice Natural regeneration Pathway interactions Pattern Phase Prevention Process Series Signal Pathway Signal Transduction Techniques Testing Tissue Engineering Tissues WNT Signaling Pathway appendage base beta catenin conditional mutant external genitalia fetal gene therapy genetic analysis global health improved in utero in vivo innovation loss of function male malformation mouse model mutant novel prenatal exposure reproductive sex development disorder transcription factor

Alleles Androgen Receptor Androgens Awareness Congenital Abnormality Development Embryonic Development Endocrine Disruptors Environmental Risk Factor Etiology Event Exposure to Fibroblast Growth Factor Receptors Foundations Frequencies Future Genes Genetic Genetic Transcription Genital system Genitalia Goals Hand Heart Abnormalities Human Hypospadias Incidence Knockout Mice Knowledge Lead Limb structure Mammals Masculine Mesenchyme Methods Molecular Genetics Molecular Profiling Morphogenesis Mus Mutant Strains Mice Natural regeneration Pathway interactions Pattern Phase Prevention Process Series Signal Pathway Signal Transduction Techniques Testing Tissue Engineering Tissues WNT Signaling Pathway appendage base beta catenin conditional mutant external genitalia fetal gene therapy genetic analysis global health improved in utero in vivo innovation loss of function male malformation mouse model mutant novel prenatal exposure reproductive sex development disorder transcription factor

展开

项目摘要

Abstract Genital malformation including hypospadias represents the second most common male birth defect after cardiac defect. In the past 50 years, hypospadias incidence has doubled along with other male reproductive problems. It is suspected that fetal exposure to endocrine disruptors may have contributed to this increase. However, the etiology of hypospadias is still largely unclear. Both environmental and genetic factors are involved. In fact, our understandings of genital development in general are still very limited. A complete understanding of genetic pathways governing genital development and masculinization and how perturbations of these pathways lead to genital malformations will have immense applications to improve global health. In the past few years, we have performed comprehensive genetic analyses on genital tubercle (GT) development in the mouse and established a conserved genetic pathway (Wnt/β-cateninSp8Fgf8) in regulating body appendage outgrowth, including limbs and external genitalia. Genetic interactions between Wnt and Shh pathways in regulating both genitalia outgrowth and masculinization have also been described. Together, these studies laid the foundation for understanding posterior embryonic development as well as how environmental factors can influence genitalia development and cause hypospadias. Based on these findings, this proposal will continue to use mouse genetics including a series of conditional mutant mice to investigate a novel genetic pathway regulating GT outgrowth. In Aim I, We will characterize several knockout mouse models to build a genetic pathway regulating GT outgrowth and patterning. In Aim II, we will use a novel and highly innovative Split DamID technique to identify in vivo downstream targets of androgen receptor and β-catenin during genital masculinization. Together, these studies should greatly improve our understanding of genitalia development and hypospadias formation. Our long term goal is to use mouse molecular genetics to understand the process of genital development and masculinization and the etiology of genital malformations, such as hypospadias.

抽象的一般畸形在内，包括催化性代表了第二大最常见的男性出生缺陷心脏缺陷。在过去的50年中，Hypospadias的发病率与其他男性生殖增加了一倍问题。怀疑胎儿暴露于内分泌干扰物可能导致了这种增加。但是，催生的病因仍然在很大程度上不清楚。环境和遗传因素都是涉及。实际上，我们对生殖器发展的理解总体上仍然非常有限。完整了解有关生殖器发展和男性化以及如何扰动的遗传途径在这些途径中，导致生殖器畸形将有巨大的应用来改善全球健康。在过去几年，我们对生殖结节（GT）发育进行了全面的遗传分析小鼠并在调节体中建立了保守的遗传途径（Wnt/β-cateninSP8FGF8）附属物的生长，包括四肢和外生殖器。 Wnt和SHH之间的遗传相互作用还已经描述了生殖器生殖器生殖器的途径和男性化的途径。一起，这些研究奠定了理解后胚胎发展以及如何环境因素会影响生殖器的发展并引起催生。基于这些发现，该建议将继续使用小鼠遗传学，包括一系列条件突变小鼠来研究新型遗传途径调节GT的生长。在AIM I中，我们将描述几种淘汰鼠标模型建立遗传途径调节GT的生长和图案。在AIM II中，我们将使用一部小说和高度创新的拆分DAMID技术以鉴定雄激素受体和β-catenin的体内下游靶标在生殖器男性化期间。这些研究总之大大改善了我们对生殖器的理解发展和催生层的形成。我们的长期目标是将小鼠分子遗传学用于了解生殖器发育和男性化的过程以及生殖器畸形的病因，例如Hypospadias。